tbuckley/cabot-search huggingface dataset:
Eosinophils protect against pulmonary hypertension through 14-HDHA and 17-HDHA
Authors: Ting Shu, Jiawei Zhang, Yitian Zhou, Zhihua Chen, Jinqiu Li, Qihao Tang, Wenqi Lei, Yanjiang Xing, Jing Wang, Chen Wang
Journal: European Respiratory Journal (2022)

Background Pulmonary hypertension (PH) is a life-threatening disease featuring pulmonary vessel remodelling and perivascular inflammation. The effect, if any, of eosinophils (EOS) on the development of PH remains unclear. Methods EOS infiltration and chemotaxis were investigated in peripheral blood and lung tissues from pulmonary arterial hypertension (PAH) patients without allergic history and from sugen/hypoxia-induced PH mice. The role of EOS deficiency in PH development was investigated using GATA1- deletion (ΔdblGATA) mice and anti-interleukin 5 antibody-treated mice and rats. Ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was conducted to identify the critical oxylipin molecule(s) produced by EOS. Culture supernatants and lysates of EOS were collected to explore the mechanisms in co-culture cell experiments. Results There was a lower percentage of EOS in peripheral blood but higher infiltration in lung tissues from PAH patients and PH mice. PAH/PH lungs showed increased EOS-related chemokine expression, mainly C-C motif chemokine ligand 11 derived from adventitial fibroblasts. EOS deficiency aggravated PH in rodents, accompanied by increased neutrophil and monocyte/macrophage infiltration. EOS highly expressed arachidonate 15-lipoxygenase (ALOX15). 14-hydroxy docosahexaenoic acid (14-HDHA) and 17-HDHA were critical downstream oxylipins produced by EOS, which showed anti-inflammatory effects on recruitment of neutrophils and monocytes/macrophages through N-formyl peptide receptor 2. They also repressed pulmonary artery smooth muscle cell (PASMC) proliferation by activating peroxisome proliferator-activated receptor γ and blunting Stat3 phosphorylation. Conclusions In PH development without external stimuli, peripheral blood exhibits a low EOS level. EOS play a protective role by suppressing perivascular inflammation and maintaining PASMC homeostasis via 14/17-HDHA.
Teprotumumab: A Review in Thyroid Eye Disease
Authors: Tina Nie, Yvette N. Lamb
Journal: Drugs (2022)

Teprotumumab (TEPEZZA®), a monoclonal antibody that inhibits the insulin-like growth factor 1 receptor (IGF-1R), is the first disease-modifying therapy approved for the treatment of thyroid eye disease (TED) in the USA. In phase II and III clinical trials in adults with active, moderate-to-severe TED, intravenous teprotumumab significantly improved proptosis response rate and a range of other TED outcomes, including overall response rate, Clinical Activity Score, diplopia and disease-specific quality of life. The clinical benefit of teprotumumab was maintained for up to 51 weeks post-treatment in the majority of patients. Teprotumumab was generally well tolerated; adverse events with the greatest risk difference compared with placebo were muscle spasms, hearing loss and hyperglycaemia. Early real-world experience suggests teprotumumab may also be beneficial in a more diverse TED population. Teprotumumab is the first approved treatment for TED and is effective at reducing symptoms which are often unamenable to historical pharmacological interventions. While further data are required, current evidence suggests teprotumumab represents an important advance in the treatment of TED. Thyroid eye disease (TED) is an inflammatory disease that involves expansion of the soft tissue surrounding and behind the eye. It can lead to bulging of the eye(s), double vision, optic nerve compression and vision loss. Traditional treatments are often unsatisfactory. Insulin-like growth factor 1 receptor (IGF-1R) signalling is implicated in the progression of TED, leading to the development of teprotumumab (TEPEZZA®). Teprotumumab, administered intravenously, is a first-in-class monoclonal antibody that inhibits IGF-1R. In clinical trials, teprotumumab was effective at improving bulging of the eye, inflammation, double vision and TED-related quality of life. Almost one year after the cessation of treatment, clinical benefits endured in most patients. Teprotumumab was generally well tolerated, with most adverse events being mild or moderate in severity. Adverse events included muscle spasms, hearing loss and hyperglycaemia. Teprotumumab is the first targeted therapy approved for TED and represents an important advance in the management of this condition.
Case 36-2022: A 30-Year-Old Woman with Decreased Vision and Headache
Authors: Michael Levy, Bart K. Chwalisz, Benjamin M. Kozak, Michael K. Yoon, Helen A. Shih, Anna M. Stagner
Journal: New England Journal of Medicine (2022)

A 30-year-old woman was evaluated for monocular vision loss. Two months earlier, during the third trimester of pregnancy, headache and decreased vision in the right eye had developed. A diagnostic procedure was performed.
Climate Change and Vectorborne Diseases
Authors: Madeleine C. Thomson, Lawrence R. Stanberry
Journal: New England Journal of Medicine (2022)

T he effects of climate change are widespread and rapidly intensifying and are largely driven by greenhouse-gas emissions from burning fossil fuels. 1 Global mean temperatures have already increased by 1.1°C since 1900, 1 with most of the change having occurred in the past 50 years.The extent of change is most extreme in highland and polar regions (Fig. 1), and temperatures in tropical regions are creeping closer to the thermal limits of many organisms.Given the current policies and actions, a warming of 2.5°C to 2.9°C or more by the end of this century is expected. 2arming and other manifestations of climate change -including changes in precipitation, with increased flooding in some areas and drought in others -have important implications for vectorborne diseases through their effects on pathogens, vectors, and hosts, as well as on our ability to prevent and treat these diseases (Fig. 2).Yet attributing changes in the distribution and frequency of vectors and diseases to climate change is challenging because other factors, including land-use changes, 3 the abundance of reservoir hosts, 4 and control measures, 5 also contribute to these changes.Furthermore, it may be difficult to distinguish between natural climate variability and human-influenced change, 6 although scientific techniques to do so are emerging.Despite these complexities, it is clear that the components of vectorborne disease systems, including pathogens, vectors, and reservoir hosts, are highly responsive to the varied environments they inhabit and that observed changes in the rates of vectorborne diseases at given locations are often associated with concomitant changes in the local climate.For example, warming temperatures affect the behavior, physiologic characteristics, and life history of both vectors and pathogens as well as the abundance and behavior of reservoir hosts and definitive hosts.The interactions among temperature, vector, and pathogen can change the risk of human-to-human disease spread and of spillover to humans from reservoir hosts.Thermal performance curves illustrate the ways in which temperature affects the physiological traits of pathogens, vectors, and reservoir hosts, which determine the rate of disease spread in a susceptible population.These curves are commonly used to predict the potential effects of rising temperatures resulting from climate change on vectorborne disease systems. 7Curves for individual components of a disease system must overlap in order for transmission to occur.Thermal adaptation, acclimation to a warming climate, or both can potentially shift thermal performance curves and thermal tolerance limits, with important implications for expansion of the geographic range of certain diseases.Depending on their ability to adapt, vectors may no longer carry certain pathogens or may carry new ones as climate-mediated ecosystem changes bring different pathogens, vectors, and reservoir and human hosts together.
The genetic and biochemical determinants of mRNA degradation rates in mammals
Authors: Vikram Agarwal, David R. Kelley
Journal: Genome biology (2022)

Abstract Background Degradation rate is a fundamental aspect of mRNA metabolism, and the factors governing it remain poorly characterized. Understanding the genetic and biochemical determinants of mRNA half-life would enable more precise identification of variants that perturb gene expression through post-transcriptional gene regulatory mechanisms. Results We establish a compendium of 39 human and 27 mouse transcriptome-wide mRNA decay rate datasets. A meta-analysis of these data identified a prevalence of technical noise and measurement bias, induced partially by the underlying experimental strategy. Correcting for these biases allowed us to derive more precise, consensus measurements of half-life which exhibit enhanced consistency between species. We trained substantially improved statistical models based upon genetic and biochemical features to better predict half-life and characterize the factors molding it. Our state-of-the-art model, Saluki, is a hybrid convolutional and recurrent deep neural network which relies only upon an mRNA sequence annotated with coding frame and splice sites to predict half-life ( r =0.77). The key novel principle learned by Saluki is that the spatial positioning of splice sites, codons, and RNA-binding motifs within an mRNA is strongly associated with mRNA half-life. Saluki predicts the impact of RNA sequences and genetic mutations therein on mRNA stability, in agreement with functional measurements derived from massively parallel reporter assays. Conclusions Our work produces a more robust ground truth for transcriptome-wide mRNA half-lives in mammalian cells. Using these revised measurements, we trained Saluki, a model that is over 50% more accurate in predicting half-life from sequence than existing models. Saluki succinctly captures many of the known determinants of mRNA half-life and can be rapidly deployed to predict the functional consequences of arbitrary mutations in the transcriptome.
Rivaroxaban treatment for six weeks versus three months in patients with symptomatic isolated distal deep vein thrombosis: randomised controlled trial
Authors: Walter Ageno, Lorenza Bertù, Eugenio Bucherini, Giuseppe Camporese, Francesco Dentali, Matteo Iotti, Gianfranco Lessiani, Roberto Parisi, Paolo Prandoni, Michelangelo Sartori, Adriana Visonà, Elisabetta Bigagli, Gualtiero Palareti
Journal: BMJ (2022)

To compare two different treatment durations of rivaroxaban in patients with symptomatic isolated distal deep vein thrombosis (DVT).Randomised, double blind, placebo controlled clinical trial.28 outpatient clinics specialising in venous thromboembolism.402 adults (≥18 years) with symptomatic isolated distal DVT.After receiving standard dose rivaroxaban for six weeks, participants were randomly assigned to receive rivaroxaban 20 mg or placebo once daily for an additional six weeks. Follow-up was for 24 months from study inclusion.The primary efficacy outcome was recurrent venous thromboembolism during follow-up after randomisation, defined as the composite of progression of isolated distal DVT, recurrent isolated distal DVT, proximal DVT, symptomatic pulmonary embolism, or fatal pulmonary embolism. The primary safety outcome was major bleeding after randomisation until two days from the last dose of rivaroxaban or placebo. An independent committee adjudicated the outcomes.200 adults were randomised to receive additional rivaroxaban treatment and 202 to receive placebo. Isolated distal DVT was unprovoked in 81 (40%) and 86 (43%) patients, respectively. The primary efficacy outcome occurred in 23 (11%) patients in the rivaroxaban arm and 39 (19%) in the placebo arm (relative risk 0.59, 95% confidence interval 0.36 to 0.95; P=0.03, number needed to treat 13, 95% confidence interval 7 to 126). Recurrent isolated distal DVT occurred in 16 (8%) patients in the rivaroxaban arm and 31 (15%) in the placebo arm (P=0.02). Proximal DVT or pulmonary embolism occurred in seven (3%) patients in the rivaroxaban arm and eight (4%) in the placebo arm (P=0.80). No major bleeding events occurred.Rivaroxaban administered for six additional weeks in patients with isolated distal DVT who had an uneventful six week treatment course reduces the risk of recurrent venous thromboembolism, mainly recurrent isolated distal DVT, over a two year follow-up without increasing the risk of haemorrhage.EudraCT 2016-000958-36; ClinicalTrials.gov NCT02722447.
Microneedle‐Assisted Transdermal Delivery of 2D Bimetallic Metal–Organic Framework Nanosheet‐Based Cascade Biocatalysts for Enhanced Catalytic Therapy of Melanoma
Authors: Jiajie Chen, Huicong Niu, Lei Guan, Zhibo Yang, Yuzhao He, Jinjin Zhao, Chengtie Wu, Yitong Wang, Kaili Lin, Yufang Zhu
Journal: Advanced Healthcare Materials (2022)

Current conventional treatments for malignant melanoma still face limitations, especially low therapeutic efficacy and serious side effects, and more effective strategies are urgently needed to develop them. Delivering biocatalysts into tumors to efficiently trigger in situ cascade reactions has shown huge potential in producing more therapeutic species or generating stronger tumoricidal effects for augmented tumor therapy. Recently, ultrathin 2D metal-organic framework (MOF) nanosheets have acquired great interest in biocatalysis owing to their large surface areas and abundant accessible active catalytic sites. Herein, an enhanced catalytic therapeutic strategy against melanoma is developed by biocompatible microneedle (MN)-assisted transdermal delivery of a 2D bimetallic MOF nanosheet-based cascade biocatalyst (Cu-TCPP(Fe)@GOD). Profiting from the constructed dissolving MN system, the loaded Cu-TCPP(Fe)@GOD hybrid nanosheets can be accurately delivered into the melanoma sites through skin barriers, and subsequently, trigger the specific cascade catalytic reactions in response to the acidic tumor microenvironment to effectively generate highly toxic hydroxyl radical (• OH) and deplete glucose nutrient for inducing the death of melanoma cells. The ultimate results prove the high melanoma inhibition effect and biosafety of such therapeutic modality, exhibiting a new and promising strategy to conquer malignant melanoma.
Tissue‐Targeted Drug Delivery Strategies to Promote Antigen‐Specific Immune Tolerance
Authors: Yuan Rui, Haleigh B. Eppler, Alexis A. Yanes, Christopher M. Jewell
Journal: Advanced Healthcare Materials (2022)

During autoimmunity or organ transplant rejection, the immune system attacks host or transplanted tissue, causing debilitating inflammation for millions of patients. There is no cure for most of these diseases. Further, available therapies modulate inflammation through nonspecific pathways, reducing symptoms but also compromising patients' ability to mount healthy immune responses. Recent preclinical advances to regulate immune dysfunction with vaccine-like antigen specificity reveal exciting opportunities to address the root cause of autoimmune diseases and transplant rejection. Several of these therapies are currently undergoing clinical trials, underscoring the promise of antigen-specific tolerance. Achieving antigen-specific tolerance requires precision and often combinatorial delivery of antigen, cytokines, small molecule drugs, and other immunomodulators. This can be facilitated by biomaterial technologies, which can be engineered to orient and display immunological cues, protect against degradation, and selectively deliver signals to specific tissues or cell populations. In this review, some key immune cell populations involved in autoimmunity and healthy immune tolerance are described. Opportunities for drug delivery to immunological organs are discussed, where specialized tissue-resident immune cells can be programmed to respond in unique ways toward antigens. Finally, cell- and biomaterial-based therapies to induce antigen-specific immune tolerance that are currently undergoing clinical trials are highlighted.
CSF tau microtubule-binding region identifies pathological changes in primary tauopathies
Authors: Kanta Horie, Nicolas R. Barthélemy, Salvatore Spina, Lawren VandeVrede, Yingxin He, Ross W. Paterson, Brenton A. Wright, Gregory S. Day, Albert A. Davis, Celeste M. Karch, William W. Seeley, Richard J. Perrin, Rama K. Koppisetti, Faris Shaikh, Argentina Lario Lago, Hilary W. Heuer, Nupur Ghoshal, Audrey Gabelle, Bruce L. Miller, Adam L. Boxer, Randall J. Bateman, Chihiro Sato
Journal: Nature Medicine (2022)

Abstract Despite recent advances in fluid biomarker research in Alzheimer’s disease (AD), there are no fluid biomarkers or imaging tracers with utility for diagnosis and/or theragnosis available for other tauopathies. Using immunoprecipitation and mass spectrometry, we show that 4 repeat (4R) isoform-specific tau species from microtubule-binding region (MTBR-tau 275 and MTBR-tau 282 ) increase in the brains of corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), frontotemporal lobar degeneration (FTLD)- MAPT and AD but decrease inversely in the cerebrospinal fluid (CSF) of CBD, FTLD- MAPT and AD compared to control and other FTLD-tau (for example, Pick’s disease). CSF MTBR-tau measures are reproducible in repeated lumbar punctures and can be used to distinguish CBD from control (receiver operating characteristic area under the curve (AUC) = 0.889) and other FTLD-tau, such as PSP (AUC = 0.886). CSF MTBR-tau 275 and MTBR-tau 282 may represent the first affirmative biomarkers to aid in the diagnosis of primary tauopathies and facilitate clinical trial designs.
TDP-43 condensates and lipid droplets regulate the reactivity of microglia and regeneration after traumatic brain injury
Authors: Alessandro Zambusi, Klara Tereza Novoselc, Saskia Hutten, Sofia Kalpazidou, Christina Koupourtidou, Rico Schieweck, Sven Aschenbroich, Lara Silva, Ayse Seda Yazgili, Frauke van Bebber, Bettina Schmid, Gabriel Möller, Clara Tritscher, Christian Stigloher, Claire Delbridge, Swetlana Sirko, Zeynep Irem Günes, Sabine Liebscher, Jürgen Schlegel, Hananeh Aliee, Fabian Theis, Silke Meiners, Michael Kiebler, Dorothee Dormann, Jovica Ninkovic
Journal: Nature Neuroscience (2022)
Impact of maximal extent of resection on postoperative deficits, patient functioning, and survival within clinically important glioblastoma subgroups
Authors: Jasper K W Gerritsen, Rosa H Zwarthoed, John L Kilgallon, Noah Lee Nawabi, Georges Versyck, Charissa A C Jessurun, Koen P Pruijn, Fleur L Fisher, Emma Larivière, Lien Solie, Rania A Mekary, Djaina D Satoer, Joost W Schouten, Eelke M Bos, Alfred Kloet, Rishi Nandoe Tewarie, Timothy R Smith, Clemens M F Dirven, Steven De Vleeschouwer, Arnaud J P E Vincent, Marike L D Broekman
Journal: Neuro-Oncology (2022)

The impact of extent of resection (EOR), residual tumor volume (RTV), and gross-total resection (GTR) in glioblastoma subgroups is currently unknown. This study aimed to analyze their impact on patient subgroups in relation to neurological and functional outcomes.Patients with tumor resection for eloquent glioblastoma between 2010 and 2020 at 4 tertiary centers were recruited from a cohort of 3919 patients.One thousand and forty-seven (1047) patients were included. Higher EOR and lower RTV were significantly associated with improved overall survival (OS) and progression-free survival (PFS) across all subgroups, but RTV was a stronger prognostic factor. GTR based on RTV improved median OS in the overall cohort (19.0 months, P < .0001), and in the subgroups with IDH wildtype tumors (18.5 months, P = .00055), MGMT methylated tumors (35.0 months, P < .0001), aged <70 (20.0 months, P < .0001), NIHSS 0-1 (19.0 months, P = .0038), KPS 90-100 (19.5 months, P = .0012), and KPS ≤80 (17.0 months, P = .036). GTR was significantly associated with improved OS in the overall cohort (HR 0.58, P = .0070) and improved PFS in the NIHSS 0-1 subgroup (HR 0.47, P = .012). GTR combined with preservation of neurological function (OFO 1 grade) yielded the longest survival times (median OS 22.0 months, P < .0001), which was significantly more frequently achieved in the awake mapping group (50.0%) than in the asleep group (21.8%) (P < .0001).Maximum resection was especially beneficial in the subgroups aged <70, NIHSS 0-1, and KPS 90-100 without increasing the risk of postoperative NIHSS or KPS worsening. These findings may assist surgical decision making in individual glioblastoma patients.
Launch meeting of the new World Health Organization Collaborating Centre for Antimicrobial Resistance, Consumption and Health Care-Associated Infections at the Robert Koch institute, Berlin, Germany, October 2022
Journal: Eurosurveillance (2022)

Preview this article: Launch meeting of the new World Health Organization Collaborating Centre for Antimicrobial Resistance, Consumption and Health Care-Associated Infections at the Robert Koch institute, Berlin, Germany, October 2022, Page 1 of 1 < Previous page | Next page > /docserver/preview/fulltext/eurosurveillance/27/47/eurosurv-27-47-3-1.gif
Preparing Europe for future health threats and crises – the European Health Emergency and Preparedness Authority; improving EU preparedness and response in the area of medical countermeasures
Authors: Pierre Delsaux
Journal: Eurosurveillance (2022)

Preview this article: Preparing Europe for future health threats and crises – the European Health Emergency and Preparedness Authority; improving EU preparedness and response in the area of medical countermeasures, Page 1 of 1 < Previous page | Next page > /docserver/preview/fulltext/eurosurveillance/27/47/eurosurv-27-47-1-1.gif
Proper wiring of newborn neurons to control bladder function after complete spinal cord injury
Authors: Fei Hao, Fan Jia, Peng Hao, Hongmei Duan, Zijue Wang, Yubo Fan, Wen Zhao, Yudan Gao, Orion R. Fan, Fuqiang Xu, Zhaoyang Yang, Yi E. Sun, Xiaoguang Li
Journal: Biomaterials (2022)

Activation of endogenous neurogenesis by bioactive materials enables restoration of sensory/motor function after complete spinal cord injury (SCI) via formation of new relay neural circuits. The underlying wiring logic of newborn neurons in adult central nervous system (CNS) is unknown. Here, we report neurotrophin3-loaded chitosan biomaterial substantially recovered bladder function after SCI. Multiple neuro-circuitry tracing technologies using pseudorabies virus (PRV), rabies virus (RV), and anterograde adeno-associated virus (AAV), demonstrated that newborn neurons were integrated into the micturition neural circuits and reconnected higher brain centers and lower spinal cord centers to control voiding, and participated in the restoration of the lower urinary tract function, even in the absence of long-distance axonal regeneration. Opto- and chemo-genetic studies further supported the notion that the supraspinal control of the lower urinary tract function was partially recovered. Our data demonstrated that regenerated relay neurons could be properly integrated into disrupted long-range neural circuits to restore function of adult CNS.
Re: Tomar et al.: American Joint Committee on Cancer Ophthalmic Oncology Task Force. High-risk pathologic features based on presenting findings in advanced intraocular retinoblastoma: a multicenter, international data-sharing American Joint Committee on Cancer Study (Ophthalmology. 2022;129:923–932) and Tomar et al.: American Joint Committee on Cancer Ophthalmic Oncology Task Force. Metastatic death based on presenting features and treatment for advanced intraocular retinoblastoma: a …
Authors: David H. Abramson, Carol L. Shields
Journal: Ophthalmology (2022)